drug discovery

Rebecca Ram

The Alliance is an exciting new collaboration, founded to address an urgent need to drive research and development, policymaking, awareness, outreach, and education into human-based methods of safety testing and biomedical research

Philippe Vanparys

In the pharmaceutical industry, toxicology testing is normally done by preclinical scientists during the Development phase. In the last decade, the implementation of high-throughput screens during the Discovery phase has resulted in an ever-increasing number of lead candidates to be selected for drug development. The low throughput of the conventional safety tests is a bottleneck in the drug-development process. The pharmaceutical industry needs new techniques, down-scaled tests and in vitro alternative test models to determine the absorption, distribution, metabolism, and excretion (ADME) and toxicology profiles of compounds in the late-Discovery phase and/or early in the Development phase. Medium-throughput ADME and toxicity tests will enhance the selection of safer new chemical entities for animals and/or humans. Consequently, this testing strategy will not only reduce the use of resources and the overall development time, but will also result in a substantial decrease in animal use.

A method for the routine, rapid and simultaneous cloning of drug targets from multiple mammalian species is described. This expedites the generation of recombinant proteins and cell lines that can provide alternatives to animal experiments. This was achieved by the collection of RNA from a comprehensive range of tissues from a variety of species, and the optimisation of cDNA synthesis. This “zooplate” has been successfully used for the simultaneous amplification and cloning of drug targets from multiple species. These products have subsequently been used to develop in vitro assays that support efficacy and safety studies in new drug discovery programmes. Within the framework of the Three Rs, these reagents can reduce the number of animals required to provide material for ex vivo assays and can refine the in vivo studies that are still necessary.

Simon Thomas

The global pharmaceutical industry is estimated to use close to 20 million animals annually, in in vivo studies which apply the results of fundamental biomedical research to the discovery and development of novel pharmaceuticals, or to the application of existing pharmaceuticals to novel therapeutic indications. These applications of in vivo experimentation include: a) the use of animals as disease models against which the efficacy of therapeutics can be tested; b) the study of the toxicity of those therapeutics, before they are administered to humans for the first time; and c) the study of their pharmacokinetics — i.e. their distribution throughout, and elimination from, the body. In vivo pharmacokinetic (PK) studies are estimated to use several hundred thousand animals annually. The success of pharmaceutical research currently relies heavily on the ability to extrapolate from data obtained in such in vivo studies to predict therapeutic behaviour in humans. Physiologically-based modelling has the potential to reduce the number of in vivo animal studies that are performed by the pharmaceutical industry. In particular, the technique of physiologically-based pharmacokinetic (PBPK) modelling is sufficiently developed to serve as a replacement for many in vivo PK studies in animals during drug discovery. Extension of the technique to incorporate the prediction of in vivo therapeutic effects and/or toxicity is less well-developed, but has potential in the longer-term to effect a significant reduction in animal use, and also to lead to improvements in drug discovery via the increased rationalisation of lead optimisation.

Katya Tsaioun and Mary Jacewicz

The advent of early Absorption, Distribution, Metabolism, Excretion, and Toxicity (ADMET) screening has increased the elimination rate of weak drug candidates early in the drug-discovery process, and decreased the proportion of compounds failing in clinical trials for ADMET reasons. This paper reviews the history of ADMET screening and why it has become so important in drug discovery and development. Assays that have been developed in response to specific needs, and improvements in technology that result in higher throughput and greater accuracy of prediction of human mechanisms of toxicity, are discussed. The paper concludes with the authors’ forecast of new models that will better predict human efficacy and toxicity.

Simon Thomas

The challenges of physiologically-based pharmacokinetic (PBPK) modelling and approaches to replacing the use of animals, in order to determine drug pharmacokinetics, are discussed. Reference is made to the limitations of in vivo animal studies in drug discovery. In particular, the ways in which animal studies contribute to drug attrition during the post-preclinical phase of testing are considered.

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ATLA is published by FRAME, and has been a key scientific journal in the field of laboratory animal alternatives for more than 30 years.
Circulated worldwide, ATLA is distributed to individuals, organisations and institutions. It covers the latest research relating to alternatives to the use of laboratory animals.